Mechanistic Understanding of Food Effects: Water Diffusivity in Gastrointestinal Tract Is an Important Parameter for the Prediction of Disintegration of Solid Oral Dosage Forms

Abstract

Much interest has been expressed in this work on the role of water diffusivity in the release media as a new parameter for predicting drug release. NMR was used to measure water diffusivity in different media varying in their osmolality and viscosity. Water self-diffusion coefficients in sucrose, sodium chloride, and polymeric hydroxypropyl methylcellulose (HPMC) solutions were correlated with water uptake, disintegration, and drug release rates from trospium chloride immediate release tablets. The water diffusivity in sucrose solutions was significantly reduced compared to polymeric HPMC and molecular sodium chloride solutions. Water diffusivity was found to be a function of sucrose concentration in the media. Dosage form disintegration and drug release was to be affected by water diffusivity in these systems. This observation can be explained by hydrogen bonding formation between sugar molecules, an effect which was not expressed in sodium chloride solutions of equal osmolality. Water diffusivity and not media osmolality in general need to be considered to predict the effect of disintegration and dissolution media on drug release. Understanding the relevance of water diffusivity for disintegration and dissolution will lead to better parametrization of dosage form behavior in gastrointestinal (GI) aqueous and semisolid media.

Justification of disintegration testing beyond current FDA criteria using in vitro and in silico models

“…SGFsp and acetate buffer pH 4.5 USP were used as conventional disintegration media, while also preparing 10%, 20% and 30% sucrose solutions as DIM. Sucrose solutions have been shown to impact tablet disintegration 29. The results from the disintegration test for the IR#2 (50 mg) formulation can be seen in Figure 8 and show a clear increase in disintegration time for the DIM compared to the conventional media, with longer disintegration times for higher sugar concentrations.…”

“…These mechanisms can also be divided into dynamic and static tablet disintegration 30,31. Sucrose solutions in particular have been shown to affect tablet disintegration both by influencing water uptake (static and dynamic disintegration) and hydrodynamics (dynamic disintegration) because of their higher viscosity, and by causing a profound depression of water diffusivity – and therefore lower water uptake – by molecular interactions (eg, hydrogen bonding) between water and sucrose 29,31…”

Understanding the mechanism of drug delivery from thickened fluids to aid swallowing of medications

“…(2012) for 1.4% HPMC and FDA meal (Radwan et al, 2013). It is considered that the values in here were unlikely to affect dissolution of a conventional dosage form delivered with water.…”

“…Cellulose polymers, or a standard food meal, added to the dissolution media decreases drug release and this has been attributed to the viscosity of the media (Radwan et al, 2013). This thesis considers the delivery of crushed tablets within structured fluid foods or thickened water, which are non-Newtonian shear thinning fluids, and undertakes detailed rheological characterisation in order to provide insights into the mechanism of drug release.…”

“…Co-administration of drugs with a meal is associated with a higher viscosity of stomach contents, which prolongs tablet disintegration time (Parojcic et al, 2008) and causes simulated oral absorption to be slower for drugs with limited permeability such as atenolol, metformin hydrochloride, furosemide and metoprolol tartrate (Cvijić et al, 2014). After ingestion of a meal, water penetration rate decreased resulting in a reduction of diffusivity which reduced disintegration and dissolution of trospium tablets (Radwan et al, 2013, Radwan et al, 2014.…”